Gilles De La Tourette's syndrome is characterized by motor and vocal tics, i.e., involuntary, sudden, rapid, recurrent, nonrhythrnic, stereotyped motor movement or vocalization. Some researchers hypothesize that there is a dysregulation in presynaptic dopamine function in Tourette's disorder (T.D.) and tics can be exacerbated by drugs that enhance synaptic dopamine function. R. T. Madison et al., Am. J. Psychiatry 152(9):1359-1361, 1995. Pharmacologic therapy has included low doses of dopamine-2 blockers and dopamine-antagonists including haloperidol, risperidone, or pimozide. T. M. Hyde et al., JAMA 273: 498-501, 1995. A problem with this dopamine-2 blockade is that this may often produce decreased attention, hyperactivity, dysphoria, and extrapyramidal symptoms in T.D. patients. Furthermore, if T.D. patients are treated with dopamine-2 stimulating analeptics (such as methylphenidate, dextroamphetamine, or pemoline) for their cognitive, attention, and hyperactivity problems, their motor and vocal tics are intensified. Non-Tourette's tic disorder most commonly arises out of previous analeptic treatment and persists after such treatment.
Posttraumatic Stress Disorder (PTSD) follows exposure to a traumatic experience involving actual or threatened death or injury or threat to the physical integrity of oneself or others. PTSD includes characteristic symptoms of reexperience, avoidance of stimuli associated with the trauma, and numbing of general responsiveness or hyperarousal (sleep difficulty, anger, difficulty concentrating, hypervigilance or exaggerated startle response) with clinically significant distress or impairment. It has been established that PTSD is associated with organic changes in the limbic system. It has also been suggested that a kindling model or a model of a paroxysmal disorder is applicable to PTSD (S. Liper et al., Psychosomatics 27 (12): 849-854, 1986). In the kindling model (R. M. Post et al, Clin. Neuropharmacol. 2:25-42, 1977), cumulative bioelectric changes, especially in the limbic area and secondary to repeated biochemical or psychological stress, can result in abnormal limbic or neuronal sensitization and major psychiatric disturbances. Pharmacologic therapy for stress disorders has included benzodiazepines (e.g., lorazepam, diazepam, clonazepam), beta adrenergic blockers and anti-seizure medications such as carbamazepine and valproic acid. It has been suggested that PTSD can induce a longlasting brainstem dysfunction resulting in loss of the normal inhibitory modulation of startle response, (E. M. Ornitz et al, Am. J. Psychiatry 146(7): 866-870, 1989) and clonidine has been used to decrease noradrenergic action and inhibit startle response. Nevertheless, no successful dramatic treatment of PTSD has been discovered for the severe, chronic cases of this crippling disorder. A number of articles describing current developments in PTSD appear in Psychiatric Annals 28:424-468, 1998.
Multiple Personality Disorder is a Dissociative Disorder which includes the existence within the person of two or more distinct personalities which recurrently take full control. There is an extensive inability to recall personal information. Dissociative disorders may occur as acute responses to overwhelming trauma and are common in combat or disasters. There is probably also a relationship between seizures and these disorders. Devinsky et al., Neurology 39:835-840, 1989.
Borderline personality disorder is characterized by tumultuous interpersonal relationships, labile mood status, and behavioral dyscontrol. Self-mutilation and violent behavior can also be seen with this disorder. Carbamazepine, an anticonvulsant with preferential action on limbic foci, produced decrease in severity of behavioral dyscontrol (R. W. Cowdry et al., Arch. Gen. Psychiatry 45:111-119, 1988) but not in the other multiple symptoms.
Primary attention deficit hyperactivity disorder (ADHD) is characterized by developmentally inappropriate failures of attention, hyperactivity, cognitive function, and impulsivity. The ADHD syndrome is idiopathic (no known secondary cause such as brain injury, dementia or known metabolic disease), begins at birth or soon thereafter, and usually has a strong hereditary basis.
Violence or rage (intermittent explosive disorder) can also be categorized as an impulse control disorder. There is a loss of control grossly out of proportion to any precipitating psychosocial stresses. Disabling outbursts of rage and violent behavior can be related to chronic brain syndrome associated with irreversible CNS (central nervous system) lesions. Yudofsky et al., Am. J. Psychiatry 138:218-220, 1981. Disorders characterized by severe episodic dyscontrol can result from brain dysfunction, e.g., resulting from a failure of modulation of electrical disturbances in the limbic system (amygdala, hippocampus, hypothalamus), temporal lobe epilepsy (TLE), brain lesions or injuries which can have neurological side effects. Other brain dysfunction disorders include motor, personality, or behavior patterns arising from, e.g., neurological impairment in the brain, TLE, viral infections, neurotransmitter disorders, amino acid imbalance, brain tumors, chromosomal abnormalities, metabolic disorders including endocrine disorders, diabetes, and genetic disorders such as disease which involves several genes, and chromosomal disorders.
Temporal lobe lesions may be brain damage produced by injury, disease, viral infection, and surgery, and can produce disturbances characterized, e.g., by seizures, which can include, e.g., motor phenomena, impairment of external awareness, depersonalization, emotional changes, behavioral disturbances, psychosis, multiple cognitive disturbances, distortions or hallucinations of any of the five senses, and autonomic disturbances (gastrointestinal, cardiac, sweating, and headache symptoms among others). The symptoms can be severe and difficult to treat. The drugs used in treatment depend on the type of seizures and have included phenytoin, carbamazepine, valproic acid, phenobarbital, primidone, felbamate, gabapentin, and lamotrigine.
Various pharmacological approaches have been taken in treating the conditions described above. For example, a number of medications such as lithium, neuroleptics, anticonvulsants, buspirone and beta blockers have been used to reduce violent behaviors as a symptom, but there are no officially labeled treatments for violent behaviors. J. Fawcett, Psychiatric Annals 27(11):725, 1997. But, particularly when the symptoms are very severe, the standard pharmacological approaches to alleviate the symptoms of episodic dyscontrol are often unsuccessful.
Temporal lobe epilepsy poses particular problems which can include simple partial seizures that can be manifested by motor symptoms, sensory symptoms, or psychic symptoms including impairment of consciousness, dysphasia, dysmnesia, illusions, and hallucinations. Complex partial seizures include impaired consciousness and psychic symptoms. The drugs used in treatment depend on the type of seizures and have included phenytoin, carbamazepine, valproic acid, phenobarbital, primidone, felbamate, gabapentin, and lamotrigine.
Temporal lobe epilepsy (TLE), and other organic brain disorders may be associated with various sexual impairments. See, e.g., D. M. Bear, "Temporal Lobe Epilepsy--A Syndrome of Sensory-Limbic Hyperconnection", Cortex 15:357-84, 1979. The most common sexual effect of organic brain problems is a loss of sexual interest and drive (hyposexuality). Less often sexual preference changes can occur and rarely fetishistic, exhibitionistic, or sadomasochistic problems occur. Some patients also develop an obsessive concern about sex and sexual performance. Treatment for these sexual problems is poor with antiepileptic or psychiatric medications but at times has been altered by unilateral temporal lobe surgery, a rather heroic procedure that many, if not most, patients are unable to undergo.
Damage to frontal lobes can also impair the executive function, that is the ability to plan, initiate, organize, carry out, monitor, and correct one's own behavior. W. W. Beatty and N. Monson, "Problem Solving By Patients With Multiple Sclerosis", Journal of the International Neurological Society 2:134-140, 1996; V. Goel and P. Grafman, "Are Frontal Lobes Involved With Planning Functions? Interpreting Data From the Tower of Hanoi", Neuropsychologia 5:623-642, 1995.
Sexual abnormalities can be associated with epilepsy or other brain diseases. These include a loss of sexual interest and drive (hyposexuality); fetishistic, exhibitionistic, or sadomasochistic problems; sexual preference changes, (homosexuality, transsexuality, or transvestism); obsessive interest in sex or sexual performance; or compulsive sexual activity. Homosexuality may become a problem for those patients who have difficulty accepting this change or who are under societal pressure. It has been long established that altered sexuality can result from various brain impairments including temporal lobe epilepsy. D. M. Bear, Cortex 15:357-384, 1979.
Huntington's Disease (H.D.) is a relatively rare (6/10,000 in U.S. and Europe) fatal neurological disorder of a hereditary nature. It is an autosomal chromosome 4 dominant disorder with full penetrance (50% chance of all children of being affected) which usually begins between age 35-40 years and kills the patient in about 15 years with severe behavioral and neurological impairments in this morbid period. There are no successful treatments of these behavioral or neurological disorders of H.D. Neither gamma amino butyric acid (GABA) agonists (i.e. carbamazepine or valproic acid) nor antipsychotic medications repair the behavioral or neurological problems of H.D. in any satisfactory fashion.
Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are similar problems of unknown cause which lead to considerable suffering and debility over 6 months or more and often for many years. The incidence is approximately 250 per 100,000 for CFS and as high as 5% of the general medical population for FM. There are no reliably successful treatments and certainly no FDA approved treatments for these two disorders. FM and CFS share in common severe fatigue, impaired concentration and memory, exercise intolerance, unrefreshing sleep, muscle and joint pain, malaise, and headaches. FM is differentiated from CFS by specific point pain spots in the muscles and CFS differs from FM by having a sore throat, tender cervical or axillary lymph nodes, variably elevated erytlirocyte sedimentation rate, occasional low grade temperature, and a variety of immunologic or neuroendocrinologic test values (none of which are consistent or indicative of any known etiologic agent) See, e.g., K. Fukuda et al., Ann. Intern. Med. 121:953-959, 1994; A. L. Komaroff et al., Rev. Infect. Dis. 13(Suppl. 1):S8-11, 1991. Both are clearly different from a depressive diagnosis. A recent study by A. L. Komaroff et al, Am. J. Med. 101:281-290, 1996, showed marked impairment of the CFS patients vs. patients with hypertension, acute myocardial infarction, multiple sclerosis, NIDDM, diabetes, congestive heart failure, or depression. Moreover, the degree and pattern of impairment CFS was different from that seen in depression. This is also the case in Fibromyalgia. L. J. Kirmayer et al., Am. J. Psychiatry 145:950-954, 1988.
Opioid or narcotic abuse or addiction, most particularly addiction to or involving the abuse of heroin, but which also may involve other opiates such as propoxyphene, meperidine, hydromorphine, codeine, levorphanol, methadone, oxycodone, morphine, hydrocodone bitartrate and other opiate derivatives, represents a major drug problem throughout the world. It probably results from at least two events: 1.) a chance or purposeful exposure of the addict or abuser to one of these opiates (either through illegal sources or medical sources) with the intake by oral, nasal, or intravenous routes, and 2.) the individual exposed may have special needs for drugs which mute pain and distress. For instance, it is an infrequent event for patients to whom narcotics are administered for medical needs to develop dependence and addiction although they may show transient tolerance during treatment or withdrawal symptoms after cessation of the treatment. The binding sites in the brain and elsewhere of these opiate drugs are similar to the sites where our own endogenous pain-relieving endorphins and enkephalins bind. It has been proposed (E. J. Khantzian, Am. J. Psychiatry 142:1259-1264, 1985) that those who abuse narcotics as a drug of choice for dependence abuse or addiction are those who are subject to disorganizing and threatening affects of rage and aggression, perhaps from inadequate responses of their own endogenous pain-relieving endorphins. Many of these patients do not feel relief of pain over time the way most other people do. Treatment results for this serious addiction problem are extremely poor, mainly because of the lack of any non-addicting drug that can relieve the craving for narcotics in these addicts. Methadone treatment has been used commonly but methadone is just another addictive opiate which can be given conveniently in an oral form. Nevertheless, methadone is frequently abused and sold for abuse by addicts and others. There are no FDA-approved non-narcotic treatments for the chronic abuse of opiate narcotics.
Sibutramine hydrochloride monohydrate (N, N-Dimethyl-1-[1-4-chlorophenyl cyclobutyl]-3-methylbutylamine hydrochloride monohydrate) available as MERIDIA.RTM. (Knoll Pharmaceutical Co., Mount Olive, N.J.) has been described for the treatment of obesity and depression (U.S. Pat. Nos. 4,746,680, 4,929,629 and 5,436,272), for diabetic hyperglycemia (WO 98/11884), and for hyperlipidemia (WO 98/13034). In contrast to many of the drugs mentioned above, sibutramine's mode of action is believed to include, among other things, inhibition of serotonin, norepinephrine, and dopamine reuptake. Accordingly, it intensifies all three of these brain neurotransmitters at their post-synaptic receptor sites. These results are described, e.g., in U.S. Pat. No. 4,939,175 which also discloses the use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine to activate the central nervous system and thereby improve certain cerebral functions involved with memory such as senile dementia, amnestic syndrome, and learning, and to increase spontaneous movement as in Parkinson's disease. There is no suggestion, however, to treat the neuropsychiatric symptoms and disorders treated according to the invention, i.e., neurological, behavioral and cognitive symptoms, particularly symptoms refractory to previous treatments.
It is an object of the invention to provide a treatment for severe secondary symptoms and disorders which often have not been successfully treated heretofore.